Proton Transfer Equilibrium Research Articles

Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation.

Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

Deciphering the degree of proton-transfer in pyrido-cyclophanes by chiroptical outcomes in non-aqueous solvents

Hydrogen position after proton transfer equilibria elucidated by diagnostic signals in ECD of cascade complexes.

Modelling biocompatible ionic liquids based on organic acids and amino acids: challenges for computational models and future perspectives.

In this short review I shall highlight the basic principle and the difficulties that arise in attempting the computational modeling of seemingly simple systems which hide an unexpected complexity. Biocompatible ionic liquids which are based on the coupling of organic or amino acid anions with metabolic cations such as cholinium are the target of this review. These substances have been the subject of intense research activities in the last few years and have attracted the attention of computational chemists. I shall show that the computational description of these substances is far from trivial and requires the use of sophisticated techniques in order to account for a surprisingly rich chemistry that is due to several phenomena such as polarization, charge transfer, proton transfer equilibria and tautomerization reactions.

Carbon Acidity in Enzyme Active Sites.

The pKa values for substrates acting as carbon acids (i.e., C-H deprotonation reactions) in several enzyme active sites are presented. The information needed to calculate them includes the pKa of the active site acid/base catalyst and the equilibrium constant for the deprotonation step. Carbon acidity is obtained from the relation pKeq = p–p = ΔpKa for a proton transfer reaction. Five enzymatic free energy profiles (FEPs) were calculated to obtain the equilibrium constants for proton transfer from carbon in the active site, and six additional proton transfer equilibrium constants were extracted from data available in the literature, allowing substrate C-H pKas to be calculated for 11 enzymes. Active site-bound substrate C-H pKa values range from 5.6 for ketosteroid isomerase to 16 for proline racemase. Compared to values in water, enzymes lower substrate C-H pKas by up to 23 units, corresponding to 31 kcal/mol of carbanion stabilization energy. Calculation of Marcus intrinsic barriers (Δ) for pairs of non-enzymatic/enzymatic reactions shows significant reductions in Δ for cofactor-independent enzymes, while pyridoxal phosphate dependent enzymes appear to increase Δ to a small extent as a consequence of carbanion resonance stabilization. The large increases in carbon acidity found here are central to the large rate enhancements observed in enzymes that catalyze carbon deprotonation.

Benzoylguanidines as Anion-Responsive Systems.

A series of benzoylguanidinium salts was prepared and the changes in UV/Vis spectra, triggered by the presence of anions, were investigated. All compounds undergo deprotonation with basic anions like dihydrogenphosphate and acetate in acetonitrile. The most pronounced spectral changes were obtained by deprotonation of N1 -benzoyl-N3 -(p-nitrophenyl) guanidinium chloride which shows the naked-eye visible color change from colorless to yellow. Measured pKa (BH+ ) in acetonitrile ranges from 12-16, which is comparable to the pyridinium cations. The proton transfer equilibria were also tested in acetonitrile/water mixture where all but the most acidic derivatives showed pKa (BH+ ) of 4-6 units which corresponds to apparent association constants of 104 -106 dm3 mol-1 . UV/Vis spectra of neutral and protonated forms were modelled by the TD-DFT approach using CAM-B3LYP and PBE0 functionals and compared to CC2 results. In the case of CAM-B3LYP, a parameter ω, defining amount of long-range exchange correction, was varied to achieve the best agreement with the experimental spectra. The optimized ω parameters are 0.10 a0 -1 for neutral benzoylguanidines and 0.20 a0 -1 for neutral nitrobenzoyl and protonated systems. The larger ω parameter in the latter is ascribed to more pronounced charge transfer character of the HOMO-LUMO transition - the one responsible for the lowest energy absorption band.

Entropy-Driven Spontaneous Reaction in Cryogenic Ice: Dissociation of Fluoroacetic Acids.

Chemical reactions are extremely difficult to occur in ice at low temperature, where atoms and molecules are frozen in position with minimal thermal energy and entropy. Contrary to this general behavior, certain weak acids including fluoroacetic acids dissociate spontaneously and more efficiently in cryogenic ice than in aqueous solution at room temperaure. The enhanced reactivity of weak acids is an unexpected consequence of proton-transfer equilibrium in ice. The configurational entropy of protons in ice shifts the acid dissociation equilibrium forward. This configurational entropy, although a solid-state property, is comparatively large in magnitude with the entropy of vaporization and can effectively drive proton-transfer reactions in ice.

Charge-transfer interaction of 4-(2-pyridylazo)resorcinol with nitroaromatics: Insights from experimental and theoretical results

Molecular charge-transfer (CT) complexation of the donor 4-(2-pyridylazo)resorcinol (1P) with selected nitroaromatic acceptors as like, 2,4-DNP, 3,5-DNSA, 3,5-DNBA, and PA have been studied in methanol at room temperature. Among the selected nitroaromatics we have isolated 1P-3,5-DNSA and 1P-PA complexes and characterized them using FT-IR, 1H NMR studies, and elemental analysis. UV–vis studies revealed that upon interaction of 1P with nitroaromatics a charge-transfer band arises which has remarkably different absorption region than the donor and the acceptor. Titrimetric studies of the ground state show the presence of one isosbestic point which also indicates the strong proton-transfer equilibrium between the molecules. Fluorescence quenching studies were also carried out to find out the Stern-Volmer binding constant (KSV) and the quenching efficiency. FT-IR and 1H NMR studies indicate that the complexation is due to the acute H-bonding interactions. Theoretical calculations (DFT) also propose the formation of the H-bonded adducts.

Ionic Strength, Surface Charge, and Packing Density Effects on the Properties of Peptide Self-Assembled Monolayers.

The various environmental parameters of packing density, ionic strength, and solution charge were examined for their effects on the properties of the immobilized peptide mimotope CH19 (CGSGSGSQLGPYELWELSH) that binds with the therapeutic antibody Trastuzumab (Herceptin) on a gold substrate. The immobilization of CH19 onto gold was examined with a quartz crystal microbalance (QCM). The QCM data showed the presence of intermolecular interactions resulting in the increase of viscoelastic properties of the peptide self-assembled monolayer (SAM). The CH19 SAM was diluted with CS7 (CGSGSGS) to decrease the packing density as CH19/CS7. The packing density and ionic strength parameters were evaluated by atomic force microscopy (AFM), ellipsometry, and QCM. AFM and ellipsometry showed a distinct conformational difference between CH19 and CH19/CS7, indicating a relationship between packing density and conformational state of the immobilized peptide. The CH19 SAM thickness was 40 Å with a rough topology, while the CH19/CS7 SAM thickness was 20 Å with a smooth topology. The affinity studies showed that the affinity of CH19 and CH19/CS7 to Trastuzumab were both on the order of 107 M-1 in undiluted PBS buffer, while the dilution of the buffer by 1000× increased both SAMs affinities to Trastuzumab to the order of 1015 M-2 and changed the binding behavior from noncooperative to cooperative binding. This indicated that ionic strength had a more pronounced effect on binding properties of the CH19 SAM than packing density. Electrochemical impedance spectroscopy (EIS) was conducted on the CH19/CS7 SAM, which showed an increase in impedance after each EIS measurement cycle. Cyclic voltammetry on the CH19/CS7 SAM decreased impedance to near initial values. The impact of the packing density, buffer ionic strength, and local charge perturbation of the peptide SAM properties was interpreted based on the titratable sites in CH19 that could participate in the proton transfer and water equilibrium.

Dynamic Acid/Base Equilibrium in Single Component Switchable Ionic Liquids and Consequences on Viscosity.

The deployment of transformational nonaqueous CO2-capture solvent systems is encumbered by high viscosities even at intermediate uptakes. Using single-molecule CO2 binding organic liquids as a prototypical example, we present key molecular features that control bulk viscosity. Fast CO2-uptake kinetics arise from close proximity of the alcohol and amine sites involved in CO2 binding in a concerted fashion, resulting in a Zwitterion containing both an alkyl-carbonate and a protonated amine. The population of internal hydrogen bonds between the two functional groups determines the solution viscosity. Unlike the ion pair interactions in ionic liquids, these observations are novel and specific to a hydrogen-bonding network that can be controlled by chemically tuning single molecule CO2 capture solvents. We present a molecular design strategy to reduce viscosity by shifting the proton transfer equilibrium toward a neutral acid/amine species, as opposed to the ubiquitously accepted zwitterionic state. The molecular design concepts proposed here are readily extensible to other CO2 capture technologies.

Probing the ESIPT process in 2-amino-1,4-naphthoquinone: thermodynamics properties, solvent effect and chemometric analysis

The developing of fluorescent probes for disease diagnosis is a very important task, which favors precision in the diagnosis and success in the treatment. Recently, amino-naphthoquinone derivatives showed to be efficient fluorescent probes for disease diagnosis. Those compounds exhibit excited-state intramolecular proton transfer (ESIPT), which is the main mechanism responsible for their use as fluorescent probes. The understanding of the ESIPT mechanism for naphthoquinones is an important way of developing more efficient and selective fluorescent probes. In this work, the ESIPT process for ANQ was performed at the TD-DFT/CAM-B3LYP/DGTZVP and DFT/B3LYP/DGTZVP level for the electronic and geometric studies. These parameters were selected for the PCA analysis. The solvent effect was investigated by using PCM and IEF-PCM in chloroform, water and methanol. 2-Amino-1,4-naphthoquinone (ANQ) showed blue emission for fluorescence, having keto–keto* absorption at 4.50 eV and the enol–enol* decay at 2.75 eV. The solvent effect was evaluated, and the ESIPT process of ANQ was favorable in nonpolar and polar solvents. Furthermore, the thermodynamics properties showed that the ESIPT is favorable with a proton transfer equilibrium constant of ~105.

Catalytic Mechanism of Mammalian Adenylyl Cyclase: A Computational Investigation.

Adenylyl cyclase (AC) catalyzes the synthesis of cyclic AMP, an important intracellular regulatory molecule, from ATP. We propose a catalytic mechanism for class III mammalian AC based on density functional theory calculations. We employ a model of the AC active site derived from a crystal structure of mammalian AC activated by Gα·GTP and forskolin at separate allosteric sites. We compared the calculated activation free energies for 13 possible reaction sequences involving proton transfer, nucleophilic attack, and elimination of pyrophosphate. The proposed most probable mechanism is initiated by deprotonation of 3'OH and water-mediated transfer of the 3'H to the γ-phosphate. Proton transfer is followed by changes in coordination of the two magnesium ion cofactors and changes in the conformation of ATP to enhance the role of 3'O as a nucleophile and to bring 3'O close to Pα. The subsequent phosphoryl transfer step is concerted and rate-limiting. Comparison of the enzyme-catalyzed and nonenzymatic reactions reveals that the active site residues lower the free energy barrier for both phosphoryl transfer and proton transfer and significantly shift the proton transfer equilibrium. Calculations for mutants K1065A and R1029A demonstrate that K1065 plays a significant role in shifting the proton transfer equilibrium, whereas R1029 is important for making the transition state of concerted phosphoryl transfer tight rather than loose.

Anchoring the Gas-Phase Acidity Scale from Hydrogen Sulfide to Pyrrole. Experimental Bond Dissociation Energies of Nitromethane, Ethanethiol, and Cyclopentadiene.

A meta-analysis of experimental information from a variety of sources is combined with statistical thermodynamics calculations to refine the gas-phase acidity scale from hydrogen sulfide to pyrrole. The absolute acidities of hydrogen sulfide, methanethiol, and pyrrole are evaluated from literature R-H bond energies and radical electron affinities to anchor the scale. Relative acidities from proton-transfer equilibrium experiments are used in a local thermochemical network optimized by least-squares analysis to obtain absolute acidities of 14 additional acids in the region. Thermal enthalpy and entropy corrections are applied using molecular parameters from density functional theory, with explicit calculation of hindered rotor energy levels for torsional modes. The analysis reduces the uncertainties of the absolute acidities of the 14 acids to within ±1.2 to ±3.3 kJ/mol, expressed as estimates of the 95% confidence level. The experimental gas-phase acidities are compared with calculations, with generally good agreement. For nitromethane, ethanethiol, and cyclopentadiene, the refined acidities can be combined with electron affinities of the corresponding radicals from photoelectron spectroscopy to obtain improved values of the C-H or S-H bond dissociation energies, yielding D298(H-CH2NO2) = 423.5 ± 2.2 kJ mol(-1), D298(C2H5S-H) = 364.7 ± 2.2 kJ mol(-1), and D298(C5H5-H) = 347.4 ± 2.2 kJ mol(-1). These values represent the best-available experimental bond dissociation energies for these species.

Gas-Phase Lithium Cation Basicity: Revisiting the High Basicity Range by Experiment and Theory

According to high level calculations, the upper part of the previously published FT-ICR lithium cation basicity (LiCB at 373 K) scale appeared to be biased by a systematic downward shift. The purpose of this work was to determine the source of this systematic difference. New experimental LiCB values at 373 K have been measured for 31 ligands by proton-transfer equilibrium techniques, ranging from tetrahydrofuran (137.2 kJ mol(-1)) to 1,2-dimethoxyethane (202.7 kJ mol(-1)). The relative basicities (ΔLiCB) were included in a single self-consistent ladder anchored to the absolute LiCB value of pyridine (146.7 kJ mol(-1)). This new LiCB scale exhibits a good agreement with theoretical values obtained at G2(MP2) level. By means of kinetic modeling, it was also shown that equilibrium measurements can be performed in spite of the formation of Li(+) bound dimers. The key feature for achieving accurate equilibrium measurements is the ion trapping time. The potential causes of discrepancies between the new data and previous experimental measurements were analyzed. It was concluded that the disagreement essentially finds its origin in the estimation of temperature and the calibration of Cook's kinetic method.

Investigating the Ritter Type Reaction of α‐Methylene‐β‐hydroxy Esters in Acidic Medium: Evidence for the Intermediacy of an Allylic Cation

AbstractThe acid‐mediated solvolytic transformation of α‐methylene‐β‐hydroxy esters in acetonitrile was investigated. The reaction was shown to involve nucleophilic attack either at the terminal methylene or at the benzylic carbon. Kinetic and theoretical studies were performed to elucidate the possible pathways involved in the formation of the acetamide products, i.e., through an addition‐elimination mechanism, a concerted process (SN2 and SN2′), or involving an allylic cation (SN1 and SN1′). The results of the kinetic analysis, including the isotope effect, Hammett plot, and Eyring plot, are in agreement with a proton transfer equilibrium prior to the formation of a benzylic carbenium ion intermediate, which is consistent with a unimolecular stepwise mechanism. Theoretical examination at the DFT level of theory corroborated these findings, with the lowest activation energy being associated with the SN1′‐type mechanism.

Quantitative dissection of hydrogen bond-mediated proton transfer in the ketosteroid isomerase active site

Hydrogen bond networks are key elements of protein structure and function but have been challenging to study within the complex protein environment. We have carried out in-depth interrogations of the proton transfer equilibrium within a hydrogen bond network formed to bound phenols in the active site of ketosteroid isomerase. We systematically varied the proton affinity of the phenol using differing electron-withdrawing substituents and incorporated site-specific NMR and IR probes to quantitatively map the proton and charge rearrangements within the network that accompany incremental increases in phenol proton affinity. The observed ionization changes were accurately described by a simple equilibrium proton transfer model that strongly suggests the intrinsic proton affinity of one of the Tyr residues in the network, Tyr16, does not remain constant but rather systematically increases due to weakening of the phenol-Tyr16 anion hydrogen bond with increasing phenol proton affinity. Using vibrational Stark spectroscopy, we quantified the electrostatic field changes within the surrounding active site that accompany these rearrangements within the network. We were able to model these changes accurately using continuum electrostatic calculations, suggesting a high degree of conformational restriction within the protein matrix. Our study affords direct insight into the physical and energetic properties of a hydrogen bond network within a protein interior and provides an example of a highly controlled system with minimal conformational rearrangements in which the observed physical changes can be accurately modeled by theoretical calculations.

Spectroscopic Studies of Amino Acid Ionic Liquid-Supported Schiff Bases

Amino acid ionic liquid-supported Schiff bases, derivatives of salicylaldehyde and various amino acids (l-threonine, l-valine, l-leucine, l-isoleucine and l-histidine) have been investigated by means of various spectroscopic techniques (NMR, UV-Vis, IR, MS) and deuterium isotope effects on 13C-NMR chemical shifts. The results have shown that in all studied amino acid ionic liquid-supported Schiff bases (except the l-histidine derivative) a proton transfer equilibrium exists and the presence of the COO− group stabilizes the proton transferred NH-form.

Spectrophotometric study of the proton transfer equilibrium between 2-aminopyridine with 2,4-dinitrophenol in methanol

2-Aminopyridine (2AP) reacts instantaneously with 2,4-dinitrophenol (DNP) in methanol to form yellow proton transfer (PT) complex at absorption maxima from 362–402 nm. The molecular composition of the PT-complex has been identified by Job's and photometric titration methods to be 1 : 1. The PT-complex formation constant (K PT) and molecular extinction coefficient (ε) were estimated by using Benesi–Hildebrand equation. They recorded high values confirming high stability of the formed complex. The stability of the formed complex was interpreted based on the formation of bifurcated and cooperative hydrogen bonds. On the basis of the rapidity of the PT-reactions, a simple and accurate spectrophotometric method for determination 2AP was proposed. Beer's law was obeyed in the concentration range 2–56 µg mL−1 with excellent correlation coefficients (0.99). Furthermore, the recovery percentage recorded 100.93%.

Acid–Base Property of N-Methylimidazolium-Based Protic Ionic Liquids Depending on Anion

Proton-donating and ionization properties of several protic ionic liquids (PILs) made from N-methylimidazole (Mim) and a series of acids (HA) have been assessed by means of potentiometric and calorimetric titrations. With regard to strong acids, bis(trifluoromethanesulfonyl) amide (Tf(2)NH) and trifluoromethanesulfonic acid (TfOH), it was elucidated that the two equimolar mixtures with Mim almost consist of ionic species, HMim(+) and A(-), and the proton transfer equilibrium corresponding to autoprotolysis in ordinary molecular liquids was established. The respective autoprotolysis constants were successfully evaluated, which indicate the proton-donating abilities of TfOH and Tf(2)NH in the respective PILs are similar. In the case of trifluoroacetic acid, the proton-donating ability of CF(3)COOH is much weaker than those of TfOH and Tf(2)NH, while ions are predominant species. On the other hand, with regard to formic acid and acetic acid, protons of these acids are suggested not to transfer to Mim sufficiently. From calorimetric titrations, about half of Mim is estimated to be proton-attached at most in the CH(3)COOH-Mim equimolar mixture. In such a mixture, hydrogen-bonding adducts formation has been suggested. The autoprotolysis constants of the present PILs show a good linear correlation with dissociation constants of the constituent acids in an aqueous phase.

Recent Advances in Spectroscopy of Hydrogen-Bonded Systems

Hydrogen bond plays a crucial role in many areas of physics, chemistry, and biology. This issue compiles five exciting papers presenting the state of the art in spectroscopic and computational aspects of hydrogen-bonded systems in three original research articles and two reviews. These papers will stimulate the continuing efforts to understand molecular interactions in hydrogen-bonded complexes, liquids and solids, the development of experimental and theoretical strategies to treat hydrogen-bonded systems, and the new evaluation of outcomes. The papers describe new methods for characterization of spectra, advances in molecular description of molecular interactions in hydrogen-bonded systems, new insights into molecular models, and current concepts in the treatment of small and large hydrogen-bonded systems. The topics include recent developments in experimental and theoretical studies of hydrogen-bonded systems, advances in theoretical models of hydrogen bonds, spectroscopy of hydrogen bonds in excited electronic states, proton transfer in hydrogenbonded complexes, photophysics of hydrogen-bonded systems, polymorphism, and dynamical aspects of hydrogen bonding. In the paper by A. Gorski et al., the authors discuss polymorphism, hydrogen bond properties, and vibrational structure of 1H-pyrrolo[3,2-h]quinoline dimers performing analysis of IR and Raman spectra, combined with DFT calculations. Theoretical investigation of the cooperativity in the CH3CHO·2H2O, CH2FCHO·2H2O, and CH3CFO·2H2O systems is presented in the paper by A. K. Chandra and T. Zeegers-Huyskens. Temperature and H/D isotopic effects in the IR spectra of the hydrogen bond in solid-state 2-furanacetic acid and 2-furanacrylic acid are discussed in the paper by H. Flakus and A. Jarczyk. L. Sobczyk et al. review proton transfer equilibria and critical behavior of H-bonding. They analyze the hydrogen bond properties of the acid-base systems depending on the ability of the proton transfer in the formulation of the Bronsted approach. M. J. Wojcik et al. present theoretical studies of dynamic interactions in excited states of hydrogenbonded systems. They present model for vibrational interactions in the hydrogen-bonded dimer of benzoic acid in electronically excited state which is used for theoretical simulation of the O–H stretching IR absorption bands and calculate tunneling splittings for vibrationally excited states in electronically excited tropolone. By compiling these papers, we hope to enrich our readers and researchers with respect to the modern problems of spectroscopy of hydrogen-bonded systems.

Proton Transfer Equilibria and Critical Behavior of H-Bonding

The aim of the present paper is an analysis of the hydrogen bond properties for the acid-base systems depending on the ability to the proton transfer in the formulation of the Brönsted approach. After definition of the proton transfer equilibrium expressed by using the equation log KPT=ξΔpKN, various examples of different physical properties, such as dipole moments, IR spectra, and nuclear magnetic resonances, are presented which correlate with the ΔpKN value. In such a way, a critical state of hydrogen bonding can be defined that corresponds to the potential of the proton motion for either single minimum or double minimum with low barrier. A particular attention in this paper found electronic spectra which have not been analysed so far and the quantitative analysis of the vibrational polarizability which can reach very high values of the order of electronic polarizability.